Abstract

Background Prior data suggest that anti-citrullinated protein/peptide antibodies (ACPA) may originate in the lung prior to the onset of synovitis in rheumatoid arthritis (RA).1 Neutrophil extracellular trap (NET) formation is one potential mechanism that could trigger or be associated with local ACPA generation because NETs externalise citrullinated proteins and release peptidylarginine deiminase that could citrullinate nearby proteins.2–4 Using induced sputum, we recently identified a significant correlation between NETs and anti-cyclic citrullinated peptide (CCP) antibodies in subjects at-risk for future RA. Herein, we sought to explore associations of individual ACPAs and NETs in these subjects.

Materials and methods From the Studies of the Aetiology of RA (SERA) cohort, we included 24 RA-free subjects At-Risk for future RA based on familial (i.e. first-degree relative of RA patient) or serologic (i.e. serum anti-CCP positive identified at health fairs) risk. Induced sputum was tested using a bead-based ACPA array for IgG reactivity to 29 individual citrullinated proteins/peptides. Levels of NET complexes in sputum were measured using a deoxyribonucleic acid (DNA)-myeloperoxidase (MPO) and DNA-neutrophil elastase (NE) sandwich ELISA. Analyses included Spearman’s correlation and linear regression. Using Bonferonni’s correction, results were considered significant if both DNA-MPO and DNA-NE assays had a p<0.002.

Conclusions In subjects At-Risk for future RA, we identified a strong correlation between sputum NET complexes and multiple sputum ACPAs that was independent of smoking exposure. These data suggest that in the lung, NET formation may be associated with the production of multiple ACPA reactivities locally. Additional studies are needed to determine if NET-associated cit-proteins are an initial trigger or a self-perpetuating stimulus of sputum ACPA generation as well as contributions of other local mechanisms of citrullination.

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